Staphylococcus aureus causes a variety of severe human diseases, including septicemia, pneumonia, toxic shock syndrome and endocarditis. Its considerable pathogenic potential results from an extensive virulence factor repertoire that includes several superantigenic toxins. The particularly high incidence of antibiotic resistance among human isolates and the potential use of staphylococcal superantigens as bioweapons further highlight the urgent need for developing effective methods for the prevention and control of this ubiquitous pathogen. Preliminary studies and previous investigations have demonstrated that a vaccine consisting of the iron-regulated protein-enriched (IRPE) fraction derived from S. aureus provides cross-protection against challenge by multiple strains of S. aureus. Furthermore, sera isolated from mice hyperimmunized with the IRPE vaccine passively protect mice against S. aureus challenge. These results led to the hypothesis that one or more of the proteins in the IRPE fraction induces the production of antibodies that are protective against S. aureus infection when administered as a passive vaccine. To test this hypothesis, and work toward the overall goal of developing safe and effective immunoprophylactic and immnotherapeutic agents to combat S. aureus infection, Phase I feasibility studies with three specific aims are proposed: Aim 1 will identify antigens in the IRPE fraction against which antibodies are raised during natural human S. aureus infection. In Aim 2, the adjuvant effect of Q136A toxoid will be evaluated in a small pilot study, and then polyclonal antibodies against individual IRPE antigens will be characterized. Finally, in Aim 3 the protective effect of the antibodies will be evaluated in vivo by infusing rabbits intravenously with antibodies before or after S. aureus challenge. Taken together, these investigations will aid in determining 1) which S. aureus antigens stimulate the production of protective antibodies and 2) the degree of protection elicited by antibody compositions raised against individual recombinant antigens. These proposed Phase I feasibility studies will provide sufficient data for the formulation of rational strategies for developing safe and effective immunoprophylactic and immunotherapeutic agents to protect against S. aureus infection. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus causes a range of severe human diseases. Although antibiotics are sometimes effective against S. aureus, antibiotic-resistant strains are becoming increasingly common. Furthermore, although several vaccine approaches are being evaluated, vaccination is not appropriate for immunocompromised patients who are often at high risk for S. aureus infections, nor is vaccination ideal when immunity is needed very quickly. As a first step toward the development of effective treatments for such patients, we herein propose to identify and characterize antibodies that protect against S. aureus infection.